A Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)

The 6 MFDs consisted of loss of communication, cortical blindness, tube feeding, total incontinence, wheelchair dependence, complete loss of voluntary movement. Month 24 MFD-Free survival criteria was defined as: alive at 24 months post-infusion; had not developed any of the MFDs by 24 months post-infusion; had not received rescue cell administration or allo-HSCT by 24 months post-infusion; and had not withdrawn from the study or had not been lost to follow-up by 24 months post-infusion. Percentage of participants who were alive and have none of the 6 major functional disabilities (MFDs) at Month 24 were reported.

Time frame: At Month 24

Population: Transplant Population (TP) consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants were defined as those who had been followed for 24 months (i.e. Rel DLC \>= 730) or have had completed Month 24, or discontinued from the study but would have been followed for 24 months if still on the study (i.e. Rel Day of data cut \>= 730).

Acute GVHD graded on the Acute GVHD Grading Scale (I-IV): Grade I is characterized as mild disease, Grade II as moderate, Grade III as severe (involvement of any organ system), and Grade IV as life-threatening; chronic GVHD was determined by the Investigator. Percentage of participants who experienced with either acute (\>= Grade II) or chronic GVHD at Month 24 were reported.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. To be evaluable participants must have either experienced the event by Month 24 (Rel Day 730) or have been followed for at least 12 months (Rel Day of DLC \>= 365) without GVHD.

Duration of ICU Stays was calculated as: Duration = (Date of hospital discharge) - (Date of hospital admission before NE) + 1. Duration of ICU Stays (Post-neutrophil Engraftment) by Month 24 was reported.

Time frame: From post-neutrophil engraftment up to Month 24

Population: The successful NEP consisted of participants who achieved NE defined as having 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion) obtained on different days of post-infusion of Lenti-D Drug Product. Here, overall number of participants analyzed signifies those participants who were evaluable for this outcome measure.

Duration of in-patient hospitalizations was calculated as: Duration = (Date of hospital discharge) - (Date of hospital admission before NE) + 1. Duration of In-patient hospitalizations (post-neutrophil engraftment) up to Month 24 was reported.

Time frame: From post-neutrophil engraftment up to Month 24

Population: The successful NEP consisted of participants who achieved NE defined as having 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion) obtained on different days of post-infusion of Lenti-D Drug Product. Here, overall number of participants analyzed signified those participants who were evaluable for this outcome measure.

MFD-free survival rate was defined as percentage of participants from drug product infusion to either second transplant, MFD, or death due to any cause, whichever occurs first. MFD-free survival rate was analyzed using Kaplan-Meier Analysis. Kaplan-Meier estimated MFD-free survival rate at 24 months after Lenti-D drug infusion was reported.

Time frame: At 24 months after Lenti-D drug infusion

Population: TP consisted of participants who received Lenti-D Drug Product infusion.

Number of emergency room visits (post-neutrophil engraftment) up to Month 24 were reported.

Time frame: From Post-Neutrophil Engraftment up to Month 24

Population: The successful Neutrophil Engraftment Population (NEP) consisted of participants who achieved NE defined as having 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion) obtained on different days of post-infusion of Lenti-D Drug Product.

Number of In-patient hospitalizations (post-neutrophil engraftment) by Month 24 were reported.

Time frame: From post-neutrophil engraftment up to Month 24

Population: The successful NEP consisted of participants who achieved NE defined as having 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion) obtained on different days of post-infusion of Lenti-D Drug Product.

Number of ICU Stays (Post-neutrophil Engraftment) By Month 24 were reported.

Time frame: From post-neutrophil engraftment up to Month 24

Population: The successful NEP consisted of participants who achieved NE defined as having 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion) obtained on different days by of post-infusion of Lenti-D Drug Product.

NFS was a 25-point score used to evaluate the severity of gross neurologic dysfunction in CALD by scoring 15 symptoms (functional domains) across 6 categories. Listed here are the 15 symptoms followed by their maximal score out of 25 points: a) Hearing / auditory processing problems-1, b) Aphasia/apraxia-1, c) Loss of communication-3, d) Vision impairment/field cut-1, e) Cortical blindness-2, f) Swallowing/other CNS dysfunctions-2, g) Tube feeding-2, h) Running difficulties/hyperreflexia-1, i) Walking difficulties/spasticity/spastic gait (no assistance)-1, j) Spastic gait (needs assistance)-2, k) Wheelchair dependence-2, l) Complete loss of voluntary movement-3, m) Episodes of incontinence -1, n) Total incontinence-2, o) Nonfebrile seizures-1. A score of 0 denoted absence of clinical signs of cerebral disease. Maximal signs within a domain score the total of all grades within that domain. Number of participants with change in total NFS from baseline up to Month 24 were reported.

Time frame: Baseline up to Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure. Evaluable participants are defined as participants who have non-missing Baseline and have completed the Month 24 NFS assessment.

Insertional oncogenesis including myelodysplasia, leukemia, lymphoma. Number of participants with insertional oncogenesis at Month 24 were reported.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion.

Number of Participants with Vector-derived RCL detected at Month 24 were reported. Screening participants blood samples for RCL at month 24 following Lenti-D Drug infusion was performed, with the more rigorous co-culture assays used to distinguish any false positives as applicable.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion.

Overall survival rate was defined as percentage of participants alive from date of Lenti-D drug product infusion (Day 0) to date of death of all causes. Overall survival rate was censored at the date of last visit if the participant were alive. Participants who are alive were censored at the date of last contact. Overall survival rate was analyzed using Kaplan-Meier Analysis. Kaplan-Meier estimated overall survival rate at 24 months after Lenti-D drug infusion was reported.

Time frame: At 24 months after Lenti-D drug infusion

Population: TP consisted of participants who received Lenti-D Drug Product infusion.

Percentage of participants who demonstrated resolution of gadolinium positivity (i.e., GdE-) on MRI at Month 24 were reported.

Time frame: At Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure. Evaluable participants are defined as participants who completed the Month 24 assessment.

Adverse event was defined as any untoward medical occurrence associated with the use of a drug product in participants, whether or not considered drug related. SAE was any AE, occurring at any dose and regardless of causality, that resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect, or was considered an important medical event that may jeopardize the participant and may require medical or surgical intervention to prevent an outcome listed previously. Percentage of participants with all AEs, all SAEs, all drug-product related AEs and SAEs Grade \>=3 (severe or medically significant but not immediately life threatening AE) and related Grade \>=3 AEs were reported.

Time frame: From date of informed consent up to Month 24

Population: ITT population consisted of participants who initiated any study procedures, beginning with mobilization by G-CSF

Laboratory parameters included hematology (Leukocytes \[with a threshold (TS) range \<4.0 x 10\^9/L, \>=18 x 10\^9/L\], Neutrophils \[\<1.0 x 10\^9/L\], Erythrocytes \[\<=3.0 x 10\^12/L\], Platelets \[\<=75 x 10\^9/L\]); clinical chemistry (Sodium \[\<=126 millimoles per liter (mmol/L), \>=156 mmol/L\], Potassium \[\<=3 mmol/L, \>=6 mmol/L\], Glucose \[\<=3.0 mmol/L\], Urea Nitrogen \[\>=10.7 mmol/L\], Creatinine \[\>=150 umol/L\]) and liver function tests (LFT) (Alanine Aminotransferase \[ALA\]. Aspartate Aminotransferase \[ASA\], Alkaline Phosphatase \[AP\] with TS range of \>=3 x upper limit of normal (ULN), Bilirubin \[\>=34.2 micromoles per liter (umol/L)\]). Clinical significance was decided by investigator.

Time frame: From time of drug product infusion up to Month 24

Population: ITT population consisted of participants who initiated any study procedures, beginning with mobilization by G-CSF.

Transplant-related mortality was determined by the Investigator in participants who had died from transplant-related causes by 100 days post-drug product infusion (Rel Day 101) or 365 days post-drug product infusion (Rel Day 366) respectively or had been followed to at least Rel Day 101 or 366 respectively if no events yet. Percentage of participants with transplant-related mortality through 100 and 365 days post-drug product infusion were reported.

Time frame: From time of drug product infusion through 100 and 365 days post-drug product infusion

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants included participants who had died from transplant-related causes by Rel Day 101 or 366 respectively or have been followed to at least Rel Day 101 or 366 respectively if no events yet.

Percentage of Participants who have undergone a subsequent allo-HSC infusion at Month 24 were reported.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Here, Overall number of participants analyzed signifies those participants who were evaluable for this outcome measure. Evaluable participants were defined as those who decided to receive subsequent allo-HSCT thus discontinued from the study, or participants who have been followed for at least 24 months (Rel Day of last contact \>= 730 or completed Month 24 visit) if no events.

Participants were considered to have primary engraftment failure if they did not achieve NE by Relative Day 43. A participant was considered to have secondary engraftment failure if they achieved and then subsequently lost NE by the Month 24, i.e., if they met both the conditions; Achieved NE by Relative Day 43 as defined above and had sustained decline in ANC to \< 0.5×10\^9 cells/L for 3 consecutive measurements on different days after Relative Day 43, without alternate etiology. First day of the 3 consecutive ANC decline to \< 0.5×10\^9 cells/L was considered the day of secondary engraftment failure. Percentage of participants with both primary and secondary engraftment failure at Month 24 were reported.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Here, Overall number of participants analyzed signified those participants who were evaluable for this outcome measure. Evaluable participants for secondary Neutrophil Engraftment failure included participants who had achieved neutrophil engraftment, and 1) have secondary engraftment failure by Rel Day 730, or 2) had been followed for at least 24 months without any events.

Neutrophil engraftment (NE) was defined as achieving 3 consecutive absolute neutrophil count (ANC) laboratory values of \>= 0.5×10\^9 cells/Liter (L) (after initial post-infusion nadir) obtained on different days by 42 days post-infusion of Lenti-D Drug Product (Relative Day 43). Percentage of participants with neutrophil engraftment by 42 Days post-drug product infusion were reported.

Time frame: By 42 days post-drug infusion

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Evaluable participants for NE if they achieved neutrophil engraftment by Rel Day 43, or had discontinued or were lost to follow-up before Rel Day 43 without achieving NE, or had been followed to at least Rel Day 43 but had not achieved NE. Participants who discontinued or were lost to follow-up before Rel Day 43 without achieving NE were considered failures for NE.

Platelet Engraftment was defined as achieving 3 consecutive unsupported platelet counts of \>=20 × 10\^9 cells/L (after initial post-infusion nadir) obtained on different days while no platelet transfusions were administered for 7 days immediately preceding and during the evaluation period. The first day of 3 consecutive platelet counts \>=20 × 10\^9 cells/L was the day of PE. Percentage of participants with Platelet Engraftment by Month 24 (Rel Day 730) were reported.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Participants were evaluable for platelet engraftment if they achieved Platelet Engraftment by 24 months (Rel Day 730), or had been followed for at least 24 months without any events.

Neutrophil Engraftment was defined as achieving 3 consecutive ANC laboratory values of \>= 0.5×10\^9 cells/L (after initial post-infusion nadir) obtained on different days by 42 days post-infusion of Lenti-D Drug Product (Relative Day 43). Time to neutrophil engraftment post-drug product infusion was reported.

Time frame: By 42 days post-drug infusion

Population: TP consisted of Participants who received Lenti-D Drug Product infusion. Participants were evaluable for NE if: 1) They achieved Neutrophil Engraftment by Rel Day 43 2)Had discontinued or were lost to follow-up before Rel Day 43 without achieving NE 3) Had been followed to at least Rel Day 43 but had not achieved NE. Participants who discontinued or were lost to follow-up before Rel Day 43 without achieving NE were considered failures for NE.

Platelet Engraftment was defined as achieving 3 consecutive unsupported platelet counts of \> or =20 × 10\^9 cells/L (after initial post-infusion nadir) obtained on different days while no platelet transfusions were administered for 7 days immediately preceding and during the evaluation period. The first day of 3 consecutive platelet counts \>=20 × 10\^9 cells/L was the day of PE. Time to Platelet Engraftment post-drug product infusion up to Month 24 was reported.

Time frame: By Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Participants were evaluable for Platelet Engraftment if they had achieved platelet engraftment by 24 months (Rel Day 730), or had been followed for at least 24 months without any events.

Sustained resolution of gadolinium positivity was defined as having at least two consecutive GdE- results by MRI without a subsequent evaluation indicating GdE+.

Time frame: Up to Month 24

Population: TP consisted of participants who received Lenti-D Drug Product infusion. Here, Overall Number of participants Analyzed signifies those participants who were evaluable for this outcome measure. Evaluable participants are defined as participants who have completed the Month 24 assessment of GdE status.